Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

ABSTRACT

Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.07114019.8 filed on Aug. 8, 2007, and which is incorporated herein byreference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to inhibitors of the phosphodiesterase 4(PDE4) enzyme. More particularly, the invention relates to compoundsthat are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods ofpreparing such compounds, compositions containing them, and therapeuticuse thereof.

2. Discussion of the Background

Airway obstruction characterizes a number of severe respiratory diseasesincluding asthma and chronic obstructive pulmonary disease (COPD).Events leading to airway obstruction include oedema of airway walls,increased mucous production and inflammation.

Drugs for treating respiratory diseases such as asthma and COPD arecurrently administered through inhalation. One of the advantages of theinhalatory route over the systemic one is the possibility of deliveringthe drug directly at site of action, avoiding any systemic side-effects,thus resulting in a more rapid clinical response and a highertherapeutic ratio.

Inhaled corticosteroids are the current maintenance therapy of choicefor asthma and together with bronchodilator beta₂-agonists for acutesymptom relief, they form the mainstay of current therapy for thedisease. The current management of COPD is largely symptomatic by meansof bronchodilating therapy with inhaled anticholinergics and inhaledbeta₂-adrenoceptor agonists. However, corticosteroids do not reduce theinflammatory response in COPD as they do in asthma.

Another class of therapeutic agents which has been widely investigatedin view of its anti-inflammatory effects for the treatment ofinflammatory respiratory diseases such as asthma and COPD is representedby the inhibitors of the enzymes phosphodiesterases (PDEs), inparticular of the phosphodiesterase type 4 (hereinafter referred to asPDE4).

Various compounds acting as PDE4 inhibitors have been disclosed in theprior art. However, the usefulness of several PDE4 inhibitors of thefirst-generation such as rolipram and piclamilast has been limited dueto their undesirable side effects. Said effects include nausea andemesis due to their action on PDE4 in the central nervous system andgastric acid secretion due to the action on PDE4 in parietal cells inthe gut.

The cause of said side effects has been widely investigated. It has beenfound that PDE4 exists in two distinct forms representing differentconformations, that were designated as high affinity rolipram bindingsite or HPDE4, especially present in the central nervous system and inparietal cells, and low affinity rolipram binding site or LPDE4 (see,Jacobitz, S. et al., Mol. Pharmacol., vol. 50, pp. 891-899 (1996)),which is found in the immune and inflammatory cells. While both formsappear to exhibit catalytic activity, they differ with respect to theirsensitivity to inhibitors. In particular compounds with higher affinityfor LPDE4 appear less prone to induce side-effects such as nausea,emesis and increased gastric secretion.

The effort of targeting LPDE4 has resulted in a slight improvement inthe selectivity for the second-generation PDE4 inhibitors such ascilomilast and roflumilast. However, even these compounds are notprovided with a good selectivity towards LPDE4.

Other classes of compounds acting as PDE4 inhibitors have been disclosedin the prior art. For example, EP 1 634 606 discloses, among others,ketone derivatives like benzofuran or 1,3-benzodioxole derivatives.

WO 9402465 discloses, among others, ketone derivatives of generalformula

wherein R₁ is lower alkyl and R₂ may be alkyl, alkenyl, cycloalkyl,cycloalkyl, cycloalkenyl, cyclothioalkyl or cyclothioalkenyl. WO 9535281in the name of Celltech Therapeutics concerns tri-substituted phenylderivatives. Both applications are silent about the problems of the sideeffects associated with inhibition of HPDE4 and do not report dataregarding affinity toward HPDE4 and LPDE4.

Therefore, although several PDE4 inhibitors have been disclosed so far,there is still a need for more efficacious and better toleratedcompounds.

In particular, it would be highly advantageous to provide more selectivecompounds, e.g. endowed with a higher affinity toward the LPDE4 withrespect to the affinity to HPDE4, in order to attenuate or avoid theside effects associated with its inhibition.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds which are useful as phosphodiesterase 4 (PDE4) inhibitors.

It is another object of the present invention to provide novel compoundswhich are useful as PDE4 inhibitors with an improved selectivity towardLPDE4.

It is another object of the present invention to provide novel compoundswhich are useful for the prevention and/or treatment of any diseasecharacterized by PDE4 overactivity and/or wherein an inhibition of PDE4activity is desirable.

It is another object of the present invention to provide novel compoundswhich are useful for the prevention and/or treatment of a disease therespiratory tract characterized by airway obstruction such as asthma andCOPD.

It is another object of the present invention to provide novel methodsof making such a compound.

It is another object of the present invention to provide novelpharmaceutical compositions which contain such a compound.

It is another object of the present invention to provide novel methodsfor the prevention and/or treatment of any disease characterized byphosphodiesterase 4 (PDE4) overactivity and/or wherein an inhibition ofPDE4 activity is desirable.

It is another object of the present invention to provide novel methodsfor the prevention and/or treatment of a disease the respiratory tractcharacterized by airway obstruction such as asthma and COPD.

The invention is provides compounds which act as inhibitors of thephosphodiesterase 4 (PDE4) enzyme, methods of preparing said compounds,compositions containing them and therapeutic use thereof.

The present invention addresses these issues by providing PDE4inhibitors having an improved selectivity toward LPDE4.

As a matter of fact, it has now been found that providing a PDE4inhibitor with an additional moiety interacting with the active site ofthe PDE4, there is an improvement in the selectivity of the inhibitorstowards LPDE4.

The PDE4 inhibitors of the present invention efficaciously act uponinhalation administration and could be characterized by a goodpersistency in the lung and a short systemic duration.

In particular the invention is directed to derivatives of1-phenyl-2-pyridinyl alkyl alcohols of general formula (I):

wherein:

Z is selected from the group consisting of

(CH₂)_(m) wherein m=0, 1 or 2;

(CH₂)_(n)O wherein n=1, 2 or 3;

O(CH₂)_(p) wherein p=0, 1, 2 or 3;

CH₂SO₂;

CHNR₆;

CH₂NR₆;

NR₆ wherein R₆ is H or a linear or branched (C₇-C₄) alkyl;

OCOR₄R₅; and

CR₄R₅ wherein

-   -   R₄ is independently selected from H or a linear or branched        (C₁-C₄) alkyl, preferably methyl, optionally substituted by a        (C₁-C₄) cycloalkyl, and    -   R₅ is independently selected from the group consisting of        -   linear or branched (C₁-C₄) alkyl, preferably methyl;        -   phenyl;        -   benzyl;        -   NH₂; and        -   HNCOOR′, wherein R′ is linear or branched (C₁-C₄) alkyl,            preferably t-butyl;

R₁ and R₂ are different or the same and are independently selected fromthe group consisting of:

H;

linear or branched (C₁-C₆) alkyl, optionally substituted by one or moresubstituents selected from (C₃-C₇) cycloalkyl or (C₅-C₇) cycloalkenyl;

(C₃-C₇) cycloalkyl;

(C₅-C₇) cycloalkenyl;

linear or branched (C₂-C₆) alkenyl; and

linear or branched (C₂-C₆) alkynyl;

R₃ is one or more substituents independently selected from the groupconsisting of H, CN, NO₂, CF₃ and halogen atoms;

A is a ring system, that is a mono- or bicyclic ring which may besaturated, partially unsaturated or unsaturated, such as aryl, (C₃-C₈)cycloalkyl or heteroaryl, said ring system A having 5 to 10 ring atomsin which at least one ring atom is a heteroatom (e.g. N, S or O), inwhich the optional substituent R_(x) on the A ring system may be one ormore, may be the same or different, and is independently selected fromthe group consisting of:

linear or branched (C₁-C₆) alkyl optionally substituted by one or more(C₃-C₇) cycloalkyl;

linear or branched (C₂-C₆) alkenyl optionally substituted by one or more(C₃-C₇) cycloalkyl;

linear or branched (C₂-C₆) alkynyl optionally substituted by one or more(C₃-C₇) cycloalkyl;

(C₅-C₇) cycloalkenyl;

phenyl;

(C₃-C₇) heterocycloalkyl; and

OR₇ wherein R₇ is selected from the group consisting of:

-   -   H;    -   (C₁-C₁₀) alkyl optionally substituted by one or more (C₃-C₇)        cycloalkyl;    -   (C₃-C₇) cycloalkyl;    -   (C₁-C₄) alkylene-(C₃-C₇) heterocycloalkyl;    -   CO (C₁-C₆) alkyl;    -   COO (C₁-C₆) alkyl;    -   phenyl;    -   benzyl;    -   (C₁-C₁₀) alkylene-NR₈R₉ wherein R₈ and R₉ are independently        selected from the group consisting of H, linear or branched        (C₁-C₆) alkyl and they form with the nitrogen atom to which they        are linked a saturated, partially saturated or unsaturated ring,        preferably NR₈R₉ is linked to (C₁-C₁₀) alkyl forming for example        saturated, partially saturated or unsaturated piperidine,        oxazine, imidazole rings, wherein these rings are optionally        substituted by (C₁-C₄) alkyl; and

halogen atoms;

CN;

NO₂;

NR₁₀R₁₁, wherein R₁₀ and R₁₁ are different or the same and areindependently selected from the group consisting of:

-   -   H;    -   linear or branched (C₁-C₆) alkyl, optionally substituted with        phenyl or (C₃-C₇) cycloalkyl;    -   COC₆H₅;    -   CO—(C₁-C₄) alkyl;    -   COO—(C₁-C₄) alkyl;    -   CONH—(C₁-C₆) alkylene-R₁₂, wherein R₁₂ is selected from the        group consisting of:        -   H;        -   (C₁-C₄) alkyl; and        -   OR₄R₅; and    -   CONH (C₁-C₄) alkylene-N(C₁-C₄) alkyl;    -   or they form with the nitrogen atom to which they are linked a        saturated or partially saturated ring, preferably a piperidyl        ring;

(C₁-C₄) alkylene-NR₁₀R₁₁;

COR₁₂ wherein R₁₂ is phenyl or linear or branched (C₁-C₆) alkyl;

oxo;

HNSO₂R₁₃ wherein R₁₃ is (C₁-C₄) alkyl or a phenyl optionally substitutedwith halogen atoms or with a (C₁-C₄) alkyl group;

SO₂R₁₄ wherein R₁₄ is (C₁-C₄) alkyl, OH or NR₁₀R₁₁ wherein R₁₀ and R₁₁are as defined above;

SOR₁₅ wherein R₁₅ is phenyl or (C₁-C₄) alkyl;

SR₁₆ wherein R₁₆ is H, phenyl or (C₁-C₄) alkyl;

COOR₁₇ wherein R₁₇ is H, (C₁-C₄) alkyl, phenyl or benzyl; and

(CH₂)_(q)OR₁₈, wherein q=1, 2, 3 or 4 and R₁₈ is H or (C₁-C₄)cycloalkyl.

and pharmaceutically acceptable salts and N-oxides on the pyridine ringthereof.

The invention also provides the pharmaceutically acceptable salts and/orsolvates thereof.

The invention further involves the corresponding N-oxides on thepyridine ring.

The invention further comprises a process for the preparation ofcompounds of general formula (I).

The present invention also provides pharmaceutical compositions whichcontain a compound of general formula (I) alone or in combination within admixture with one or more pharmaceutically acceptable carriers.

In a further aspect the present invention provides the use of thecompounds of general formula (I) as a medicament.

In a further aspect the present invention provides the use of thecompounds of general formula (I) for the manufacture of a medicament.

In particular, the present invention provides methods for the preventionand/or treatment of any disease characterized by phosphodiesterase 4(PDE4) overactivity and/or wherein an inhibition of PDE4 activity isdesirable by administering a compound of formula (I) or a salt orN-oxide thereof.

In particular the compounds of general formula (I) alone or combinedwith other active ingredients may be administered for the preventionand/or treatment of a disease the respiratory tract characterized byairway obstruction such as asthma and COPD.

In a further aspect the present invention provides the use of compoundsof general formula (I) for the preparation of a medicament for theprevention and/or treatment of an inflammatory disease, disorder orcondition characterized by or associated with an undesirableinflammatory immune response or induced by or associated with anexcessive secretion of TNF-α and PDE4.

Moreover the present invention provides a method for prevention and/ortreatment of any disease wherein PDE4 inhibition is required, saidmethod comprises administering to a patient in need of such treatment atherapeutically effective amount of a compound of general formula (I).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the context of the present invention, the term “halogen atoms” asused herein includes fluorine, chlorine, bromine, and iodine, preferablychlorine.

As used herein, the expression “linear or branched (C₁-C_(x)) alkyl”where x is an integer greater than 1, refers to straight-chained andbranched alkyl groups wherein the number of constituent carbon atoms isin the range 1 to x. Particular alkyl groups are methyl, ethyl,n-propyl, isopropyl and t-butyl. Optionally in said groups one or morehydrogen atoms can be replaced by halogen atoms, preferably chlorine orfluorine.

The derived expressions “(C₂-C₆) alkenyl” and “(C₂-C₆) alkynyl”, are tobe construed in an analogous manner.

As used herein, the expression “(C₃-C_(x)) cycloalkyl”, where x is aninteger greater than 3, refers to cyclic non-aromatic hydrocarbon groupscontaining from 3 to x ring carbon atoms. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Optionally in saidgroups one or more hydrogen atoms can be replaced by halogen atoms,preferably chlorine or fluorine.

As used herein, the expression “(C₃-C₇)heterocycloalkyl”, refers tocyclic non-aromatic hydrocarbon groups containing one or moreheteroatoms (e.g. N, S or O), optionally substituted by one or more(C₁-C₄) alkyl.

The derived expressions “(C₁-C_(x) cycloalkoxyl” is to be construed inan analogous manner.

The derived expression “(C₅-C_(x) cycloalkenyl”, where x is an integergreater than 5, is to be construed in an analogous manner.

As used herein, the expression “ring system” refers to mono- or bicyclicring systems which may be saturated, partially unsaturated orunsaturated, such as aryl, (C₃-C₈) cycloalkyl or heteroaryl, having 5 to10 ring atoms in which at least one ring atom is a hereoatom (e.g. N, Sor O). Examples of suitable monocyclic systems include phenyl, pyridyl,piperazinyl, piperidinyl, morpholinyl, cyclopentyl, cyclohexyl,cyclohexenyl, cycloheptyl, dioxane, imidazole and imidazolidine.

Examples of suitable bicyclic systems include naphthyl, quinolinyl,isoquinolinyl, indenyl, fluorene, benzimidazole, benzimidazolidine,xanthine and the partially- or fully-hydrogenated derivatives thereof.

The invention provides a class of compounds acting as inhibitors of thephosphodiesterase 4 (PDE4) enzyme. Said class of compounds inhibits theconversion of cyclic nucleotides, in particular cyclic adenosinemonophosphate (cAMP), into their inactive 5′-mononucleotide forms.

In the airways, the physiological responses to elevated intracellularlevels of cyclic nucleotides, in particular of cAMP, lead to thesuppression of the activity of immune and pro-inflammatory cells such asmast cells, macrophages, T lymphocytes, eosinophils and neutrophils,resulting in a decrease of the release of inflammatory mediators whichinclude cytokines such as IL-1, IL-3 and tumor necrosis factor-alpha(TNF-α).

It also leads to an airway smooth muscle relaxation and a decrease inoedema.

The catalytic site of PDE4 has been previously identified: it mainlycomprises a hydrophobic region in which two sub-pockets are present,e.g. S_(o) and S₁, and a hydrophilic region containing the metal ionsZn²⁺ and Mg²⁺, that in turn comprises the sub-pocket S₂ spreading aroundthe metal ions and a sub-pocket S₃ which branches approximately 90° fromthe middle of the hydrophobic pocket.

Most of the compounds of the prior art are provided with a moiety ableof interacting with the sub-pockets S₀ and S₁ of the hydrophobic regionsuch as a substituted cathecol group and with another moiety able ofindirectly interacting with the metal ions of the S₂ sub-pocket, forexample a heterocycle such as pyridine or pyrrolidone.

The present invention is directed to compounds which were designed sothat they could maintain the interactions with the sub-pockets S₀ and S₁by means of the substituted catecol moiety and the interaction with themetal ions region by means of the pyridine ring like other known PDE4inhibitors but differ for the presence of a further group able ofestablishing an additional interaction with the sub-pocket S₃.

In particular the present invention relates to derivatives of1-phenyl-2-pyridinyl alkyl alcohols of general formula (I)

Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid.

It will be apparent to those skilled in the art that the compounds ofgeneral formula (I) may contain asymmetric centers. Therefore theinvention also includes the optical stereoisomers and mixtures thereof.

Where the compounds according to the invention have at least oneasymmetric center, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccenters, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The compounds of general formula (I) were found to show an in vitroinhibitory activity toward the PDE4 enzyme in the nM range and theyturned out to be endowed of a good activity in the lungs uponintra-tracheal administration in an animal model of COPD. They alsoexhibited in some cases sustained pulmonary levels in the lungs, whileno detectable plasmatic levels were found which is an index of a shortsystemic action.

One possible explanation for the unexpectedly high selectivity of thesecompounds for LPDE4 in comparison to HPDE4 is that they all feature amoiety which could fit into the S₃ sub-pocket of the catalytic site ofthe PDE4 enzyme through the A substituent.

As it can be appreciated from the results reported in the Example 13, acompound representative of the invention was indeed found about1319-fold more selective toward LPDE4 versus HPDE4.

A preferred group of compounds of general formula (I) is that whereinthe 2-pyridinyl ring is substituted in 3 and 5 with two atoms ofchlorine, according to the general formula (II)

wherein R₁, R₂, Z and A are as defined above.

Advantageously when R₁ or R₂ is H, the other substituent on the cathecolgroup is different from H.

Preferably R₁ and R₂ are both different from H.

A first group of more preferred compounds of general formula (II) isthat in which:

R₁ and R₂ are as defined above;Z is (CH₂)_(n) wherein n is 0; andA is as defined above.

A second group of more preferred compounds is that in which:

R₁ and R₂ are as defined above;Z is CHR₅ wherein R₅ is linear or branched (C₁-C₄) alkyl, preferablymethyl; andA is as defined above.

A third group of more preferred compounds is that in which:

R₁ and R₂ are as defined above;Z is CR₄R₅ wherein R₄ and R₅ are both linear or branched (C₁-C₄) alkyland they form a ring together with the carbon atom to which they arelinked having 3, 4, 5 or 6 carbon atoms, preferably having 3 carbonatoms; andA is as defined above.

In one of the preferred embodiments, A is substituted with Rx, and Rx isselected from the group consisting of linear or branched (C₁-C₆) alkyl,linear or branched (C₂-C₆) alkenyl, linear or branched (C₂-C₆) alkynylor OR₇ wherein R₇ is as defined above.

In another preferred embodiment A is substituted with Rx, and R_(x) is agroup capable of improving the aqueous solubility of the whole moleculesuch as NR₁₀R₁₁ or HNSO₂R₁₃ wherein R₁₀, R₁₁ and R₁₃ are as definedabove.

In a particular embodiment of the invention, when A is a heteroarylring, the ring is preferably selected from the group consisting ofpyrrole, pyrazole, furan, thiophene, imidazole, oxazole, isoxazole,thiazole, pyridine, pyrimidine, pyrazine and pyran, imidazole,imidazolidine and more preferably pyridine.

According to a preferred embodiment the present invention provides thecompounds reported below:

Compound Chemical name 1 2-(4-isobutyl-phenyl)-propionic acid2-(3,5-dichloro-pyridin-4-yl)-1-(3,4- dimethoxy-phenyl)-ethyl ester 2phenyl-acetic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 3 1-phenyl-cyclopropanecarboxylic acid2-(3,5-dichloro-pyridin-4-yl)-1- (3,4-dimethoxy-phenyl)-ethyl ester 43,4-dimethoxy-benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 5(S)-tert-butoxycarbonylamino-phenyl-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 6(R)-tert-butoxycarbonylamino-phenyl-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 7(S)-amino-phenyl-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 8(R)-amino-phenyl-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 92-(4-isobutyl-phenyl)-propionic acid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 113-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester 12 2-(4-isobutyl-phenyl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 132-(4-isobutyl-phenyl)-propionic acid2-(3,5-dichloro-1-oxy-pyridin-4-yl)- 1-(3,4-dimethoxy-phenyl)-ethylester 14 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 15 2-(4-isobutyl-phenyl)-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester16 2-(4-amino-phenyl)-propionic acid2-(3,5-dichloro-pyridin-4-yl)-1-(3,4- dimethoxy-phenyl)-ethyl ester 172-(4-methanesulfonylamino-phenyl)-propionic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 254-(2-piperidin-1-yl-ethoxy)-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester26 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 274-(2-piperidin-1-yl-ethoxy)-benzoicacid 2-(3,5-dichloro-1-oxy-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 28 isonicotinic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 29 nicotinic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 304-(2-imidazol-1-yl-ethoxy)-benzoic acid 1-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester31 1-(2-{4-[1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethoxycarbonyl]-phenoxy}-ethyl)-1-methyl-piperidinium 32 4-(2-morpholin-4-yl-ethoxy)-benzoicacidcyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester33 4-difluoromethoxy-3-(2-piperidin-1-yl-ethoxy)-benzoic acid 2-(3,5-dichloro-1-oxy-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 342-(6-methoxy-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 354-(3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yloxy)-benzoicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 363-cyclopropylmethoxy-4-(2-piperidin-1-yl-ethoxy)-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 37 2-(6-methoxy-naphthalen-2-yl)-propionicacid 2-(3,5-dichloro-1-oxy- pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethylester 38 2-(6-methoxy-naphthalen-2-yl)-propionic acid2-(3,5-dichloro-pyridin-4- yl)-1-(3,4-dimethoxy-phenyl)-ethylester 392-(6-methoxy-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 404-amino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 412-(4-amino-phenyl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester42 4-amino-benzoic acid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 43 4-dimethylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester44 terephthalic acid mono-[1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl] ester 453-dimethylamino-4-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-y])-ethyl ester46 4-imidazol-1-yl-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester47 4-dimethylaminomethyl-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester48 1-methyl-1H-imidazole-4-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester49 4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester50 3-(cyclopropylmethyl-methyl-amino)-4-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 514-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 52 1,2-dimethyl-1H-benzoimidazole-5-carboxylicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 53 quinoline-3-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 54(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 55 hexadecanoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 56 pentanoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 583-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 59 4-(3-cyclopropylmethyl-ureido)-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester60 quinoline-8-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 613-cyclopropylmethoxy-4-dimethylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 62 4-[3-(2-methoxy-ethyl)-ureido]-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester63 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 64 2-(2-fluoro-biphenyl-4-yl)-propionicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester65 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 66 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 67 2-(6-dimethylamino-naphthalen-2-yl)-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 682-(6-dimethylamino-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 693-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 704-(3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester 71 4-(3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 72 acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 73 phenyl-acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 74 butyric acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 75 4-phenyl-butyric acid1-(3-cyclopropylmethoxydifluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 764-[3-(2-dimethylamino-ethyl)-ureido]-benzoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 77 6-dimethylamino-naphthalene-2-carboxylic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 78 acetoxy-phenyl-acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 791-(3-Methanesulfonylamino-4-methoxy-phenyl)-cyclopropanecarboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 801-[3-(Cyclopropylmethyl-methyl-amino)-4-methoxy-phenyl]-cyclopropanecarboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester81 oxy-benzoic acid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 822,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 83 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid2-(3,5-dichloro-pyridin-4-yl)-1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethyl ester 843-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl ester 853,4,5-triethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 864-fluoro-3-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 871-methoxy-naphthalene-2-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 883,4,5-trifluoro-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 892-(2-fluoro-biphenyl-4-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester90 2-oxo-thiazolidine-4-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester91 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 921-cyclopropylmethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethyl ester 931-(3′,4′-dichloro-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 942,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 95 6-dimethylamino-naphthalene-2-carboxylicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 96 1-cyclopropylmethyl-1H-indole-5-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 974,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 98 2-benzyloxy-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 99(3,4-dimethoxy-phenylsulfanyl)-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester100 4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 1014-[9-(4-ethyl-phenoxy)-nonyloxy]-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester

Advantageously the compounds of the invention are characterized byselectivity toward LPDE4 higher than that toward HPDE4 as obtained bythe determination of their IC₅₀. In the case of LPDE4, the IC₅₀ is themolar concentration of the test compound producing 50% inhibition ofcAMP disappearance, assessed as described in Cortijo, J. et al., Br. J.Pharmacol., 1993, 108: 562-568, while in the case of HPDE4, the IC₅₀ isthe molar concentration of the test compound producing 50% inhibition ofthe binding of [H³] rolipram, assessed as described in Duplantier, A. J.et al., J. Med. Chem., 1996; 39: 120-125. Preferably the HPDE4/LPDE4IC₅₀ ratio for the compounds of the invention is higher than 5,preferably higher than 10, more preferably higher than 20 and even morepreferably higher than 100.

The compounds of general formula (I) may be prepared conventionallyaccording to methods disclosed in the art. Some of the processes whichcan be used are described below and reported in Scheme 1 and should notbe viewed as limiting the scope of the synthetic methods available forthe preparation of the compounds of the invention.

For instance, according to a particular embodiment of the presentinvention (scheme 1), the compounds of general formula (5) may beprepared according to a process which includes the following steps:

1^(st) step—Reducing an ethanone derivative of general formula (1) togive an alcohol derivative of general formula (2) (route A). Thereaction may be carried out by using sodium boron hydride (NaBH₄) in asolvent such as methanol at room temperature under nitrogen atmosphere.

2^(nd) step—Adding a suitable acid of formula AZCOOH to a solution ofthe alcohol derivative of general formula (2) to give a compound ofgeneral formula (5). The reaction is carried out in the presence of asuitable strong base such as lithium diisopropylamide (LDA), NaH,dimethylaminopyridine (DMAP) and in the presence of a condensing agentsuch as 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride(EDC) and N-hydroxybenzotriazole (HOBT) in a solvent such asdichloromethane under nitrogen atmosphere. Other solvents may be used,such as dimethylformamide (DMF), tetrahydrofuran (THF), chloroform,dioxane and any other aprotic solvent known to those skilled in the art.In a particular embodiment, the reaction may also be carried out inabsence of solvents.

In case the carboxylic acid A-Z—COOH bears reactive groups likehydroxyl, carboxyl, thio or amino groups, they may need to be protectedby protecting groups such as t-butoxycarbonyl, benzyl,benzyloxycarbonyl, methyl, trimethylsilyl and similar and, at a certainstep of the synthesis, deprotected to obtain again the free reactivegroup; the deprotected group may be then reacted with suitable reagentslike alkylating, acylating, sulphonylating agents or similar.

The protection and deprotection of functional groups is described inProtective Groups in Organic Chemistry, 3rd edition, T. W. Greene and P.G. M. Wuts, Wiley-Interscience (1999) and Protecting Groups, P. J.Kocienski, Georg Thieme Verlag (1994).

Compounds of general formula (5) may be also prepared by adding asuitable acyl chloride of general formula A-Z—COCl or a suitableisocyanate of general formula A-Z—NCO to a solution of the alcoholderivative of general formula (2), with a suitable base in astoichiometric or a catalytic amount, according to procedures well knownto the skilled person.

The alcohol derivative of general formula (2) may alternatively beprepared by reacting a benzaldehyde derivative of formula (3) with amethylpyridine derivative of formula (4) (route B) usinglithium-bis-(trimethylsilyl)-amide (LiHMDS) or similar strong bases anda solvent such as tetrahydrofuran (THF) or other aprotic solvents.Intermediates of general formula (3) and (4) are commercially availableor may be prepared according to methods available in the literature andwell known to the person skilled in the art.

The N-oxides on the 2-pyridinyl ring of the compounds of general formula(5) may be prepared according to methods available in the literature andwell known to the skilled person. For instance they may be prepared bydissolving the compound of general formula (5) in CH₂Cl₂ or CHCl₃, thenadding an oxidizing agent such as m-chloro perbenzoic acid (mCPBA) tothe resulting solution. Other oxidizing agents which may be used arehydrogen peroxide, perbenzoic acid and peracetic acid.

For those compounds in which A is a ring substituted with a functionalgroup sensitive to oxidation, the corresponding N-oxides arealternatively prepared by carrying out the oxidation step before the2^(nd) step of the route A.

The present invention also provides pharmaceutical compositions ofcompounds of general formula (I) in admixture with one or morepharmaceutically acceptable carriers, for example those described inRemington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y.,U.S.A.

Administration of the compounds of the present invention may beaccomplished according to patient needs, for example, orally, nasally,parenterally (subcutaneously, intravenously, intramuscularly,intrasternally and by infusion), by inhalation, rectally, vaginally,topically, locally, transdermally, and by ocular administration. Varioussolid oral dosage forms may be used for administering compounds of theinvention including such solid forms as tablets, gelcaps, capsules,caplets, granules, lozenges and bulk powders. The compounds of thepresent invention may be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms may also be used for administering thecompounds of the invention, including aqueous and non-aqueous solutions,emulsions, suspensions, syrups, and elixirs. Such dosage forms can alsocontain suitable inert diluents known in the art such as water andsuitable excipients known in the art such as preservatives, wettingagents, sweeteners, flavorants, as well as agents for emulsifying and/orsuspending the compounds of the invention. The compounds of the presentinvention may be injected, for example, intravenously, in the form of anisotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention may be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration may be in the form of cream,gel, paste, foam, or spray formula containing, in addition to the activeingredient, such suitable carriers as are known in the art.

For topical administration the pharmaceutical composition may be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

For the treatment of the diseases of the respiratory tract, thecompounds according to the invention are preferably administered byinhalation. Inhalable preparations include inhalable powders,propellant-containing metering aerosols or propellant-free inhalableformulations.

For administration as a dry powder, single- or multi-dose inhalers knownfrom the prior art may be utilized. In that case, the powder may befilled in gelatine, plastic or other capsules, cartridges or blisterpacks or in a reservoir.

A diluent or carrier, generally non-toxic and chemically inert to thecompounds of the invention, e.g. lactose or any other additive suitablefor improving the respirable fraction may be added to the powderedcompounds of the invention.

Inhalation aerosols containing propellant gas such as hydrofluoroalkanesmay contain the compounds of the invention either in solution or indispersed form. The propellant-driven formulations may also containother ingredients such as co-solvents, stabilizers and optionally otherexcipients.

The propellant-free inhalable formulations comprising the compounds ofthe invention may be in form of solutions or suspensions in an aqueous,alcoholic or hydroalcoholic medium and they may be delivered by jet orultrasonic nebulizers known from the prior art or by soft-mistnebulizers such as Respimat®.

The compounds of the invention may be administered as the sole activeagent or in combination with other pharmaceutical active ingredientsincluding those currently used in the treatment of respiratorydisorders, e.g. beta₂-agonists, corticosteroids and anticholinergic orantimuscarinic agents.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular disease to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, and pharmacokinetic profile of the compound.

Advantageously, the compounds of general formula (I) may be administeredfor example, at a dosage comprised between 0.001 and 1000 mg/day,preferably between 0.1 and 500 mg/day.

When they are administered by inhalation route, the dosage of thecompounds of general formula (I) is advantageously comprised between0.01 and 20 mg/day, preferably between 0.1 and 10 mg/day.

Preferably, the compounds of general formula (I) alone or combined withother active ingredients may be administered for the prevention and/ortreatment of any obstructive respiratory disease such as asthma, chronicbronchitis and chronic obstructive pulmonary disease (COPD).

However the compounds of general formula (I) may be administered for theprevention and/or treatment of any disease wherein PDE4 inhibition isrequired. Such diseases include: allergic disease states such as atopicdermatitis, urticaria, allergic rhinitis, allergic conjunctivitis,vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatoryarthritis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock, cystic fibrosis, arterialrestenosis, artherosclerosis, keratosis, rheumatoid spondylitis,osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic andallergic contact eczema, atopic eczema, seborrheic eczema, lichensimplex, sunburn, pruritis in the anogenital area, alopecia areata,hypertrophic scars, discoid lupus erythematosus, systemic lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune diseases and the like.

They also include neurological and psychiatric disorders such asAlzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS),multiple systems atrophy (MSA), schizophrenia, Parkinson's disease,Huntington's disease, Pick's disease, depression, stroke, and spinalcord injury.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Preparation of 3,5-dichloro-4-methylpyridine(Intermediate (4) of Scheme 1)

Diisopropylamine (70 mL, 500 mmol) was dissolved in dry tetrahydrofuran(THF) (500 mL), the solution was cooled to −10° C. and buthyl lithium(2.5 N in hexane, 210 mL, 525 mmol) was added dropwise under stirring.After 30 minutes the solution was cooled to −20° C. and3,5-dicholopyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) wasadded dropwise. The solution was stirred at −10° C. for 30 minutes,cooled to −70° C. and added dropwise with iodomethane (50 mL, 1.6 mol)in tetrahydrofuran (100 mL). The reaction mixture was allowed to warm toroom temperature, quenched with water (100 mL) and extracted withdiethyl ether (3×100 mL); the combined organic layers were dried oversodium sulphate (5 g) and evaporated to dryness. The crude product wascrystallized twice from aqueous ethanol than from hexane to afford3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68% yield) as a whitesolid.

MS/ESI⁺ 162-164-166 m/z [MH]⁺.

Example 2 Preparation of2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone(Intermediate (1) of Scheme 1)

A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in drytetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 Msolution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3mmol) was added dropwise under stirring, keeping the temperature below−70° C. The resulting solution was stirred for 30 min., then a solutionof 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in drytetrahydrofuran (20 ml) was added dropwise, maintaining the temperaturebelow −70° C. After stirring for 15 minutes, ice (20 g) was added,followed by further 500 ml of water. The mixture was extracted withethyl acetate (2×50 ml), the combined organic layers were dried oversodium sulphate and evaporated under reduced pressure to give an oilthat was purified by flash chromatography (Eluent:ethylacetate/petroleum ether from 10/90 to 30/70 v:v). 2.1 grams (6.4 mmol,52% yield) of the title compound were obtained as a white solid.

MS/ESI⁺ 326-328-330 m/z [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ3.91 and 3.95 (2s, 6H), 4.62 (s, 2H), 6.91-6.95 (d, 1H), 7.53-7.54 (d,1H), 7.67-7.75 (dd, 1H), 8.49 (s, 2H).

The following intermediates were prepared using said route with suitablesolvents:

TABLE 1

Inter- mediate R₁ R₂ R₃ Analytical 1 Me cyclopentyl 3,5 MS/ESI⁺326-328-330 dichloro [MH]⁺ 1a Me cyclopropylmethyl 3,5 MS/ESI⁺366-368-370 dichloro [MH]⁺ 1b difluoro- cyclopropylmethyl 3,5 MS/ESI⁺402-404-406 methyl dichloro [MH]⁺ 1c difluoro- difluoromethyl 3,5MS/ESI⁺ 398-400-402 methyl dichloro [MH]⁺ 1d difluoro- Me 3,5 MS/ESI⁺362-366-368 methyl dichloro [MH]⁺ 1e difluoro- cyclopentyl 3,5 MS/ESI⁺416-418-420 methyl dichloro [MH]⁺

Example 3 Preparation of2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol(Intermediate (2) of Scheme 1) Route A.

Sodium boron hydride NaBH₄ (45.2 mg, 2.5 eq.) is added to a suspensionof 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone (150mg, 1 eq.) in CH₃OH (5 ml), at room temperature under nitrogenatmosphere. The mixture is stirred at room temperature overnight, thenthe reaction is quenched with water and extracted with EtOAc. Theorganic layer is dried over Na₂SO₄ and the solvent is evaporated. Thecrude is purified by flash chromatography on silica gel in gradientelution from petroleum ether/EtOAc 9/1 v/v to petroleum ether/EtOAc 7/3v/v, to obtain 75 mg of the title compound (50% yield).

MS/ESI⁺ 328-330-332[MH]⁺

The following intermediates were prepared using said route with suitablesolvents:

TABLE 2

Inter- mediates R₁ R₂ R₃ Analytical 2 Me cyclopentyl 3,5-dichloroMS/ESI⁺ 328- 330-332 [MH]⁺ 2a Me cyclopropylmethyl 3,5-dichloro MS/ESI⁺368- 370-372 [MH]⁺ 2b difluoromethyl cyclopropylmethyl 3,5-dichloroMS/ESI⁺ 404- 406-408 [MH]⁺ 2c difluoromethyl difluoromethyl 3,5-dichloroMS/ESI⁺ 400- 402-404 [MH]⁺ 2d difluoromethyl Me 3,5-dichloro MS/ESI⁺364- 368-370 [MH]⁺

Example 4 Preparation of2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol(Intermediate (2) of Scheme 1) Route B.

3,5-Dichloro-4-methylpyridine (500 mg, 1 eq.) is dissolved in dry THF (2mL) under nitrogen atmosphere at −60° C. LiN(TMS)₂ (1.0M in THF, 3.38mL, 1.1 eq.) is added dropwise via syringe, keeping the temperaturebelow −55° C. The mixture turns yellow and is stirred at −60° C. forabout 30 minutes. Then a solution of 3,4-dimethoxybenzaldehyde (513 mg,1 eq.) in dry THF (2 mL) is added dropwise via syringe, keeping thetemperature below −55° C. After the addition the mixture is slowlywarmed to room temperature and stirred at room temperature for about 2hours. Then it is quenched with water and extracted with EtOAc. Theorganic layer is dried over Na₂SO₄ and the solvent is evaporated. Thecrude is triturated with Et₂O, and filtered to obtain 741 mg of thetitle compound as a white solid (73% yield). MS/ESI⁺ 328-330-332 [MH]⁺

Example 5 Preparation of (S)-2-(4-isobutyl-phenyl)-propionic acid2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester(Compound 1)

(1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) (EDC.HCl)(345 mg, 3 eq.) is added to a solution of2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol (200 mg,1 eq.), (S)-2-(4-isobutyl-phenyl)-propionic acid (148 mg, 1.2 eq.) and4-dimethylaminopyridine (DMAP) (37 mg, 0.5 eq.) in dry CH₂Cl₂ (8 mL) atroom temperature under nitrogen atmosphere. The mixture is stirred atroom temperature overnight, then it is treated with a saturated solutionof NH₄Cl (20 ml) and extracted with EtOAc (2×20 ml). The combinedorganic layer are dried over Na₂SO₄ and the solvent is evaporated. Thecrude is purified by flash chromatography on silica gel in gradientelution (from petroleum ether/EtOAc 9/1 v/v to petroleum ether/EtOAc 7/3v/v) to yield 259 mg of pure compound.

The following compounds were prepared using said route with suitablereagents:

TABLE 3

Compound R₁ R₂ Z—A Analytical 1 Me Me

MS/ESI⁺ 516-518-520 [MH]⁺; 1H NMR (CDCl₃ calibrated at 7.26 ppm, mix ifdiast.)δ: 8.47 and 8.31(s*, 1H); 7.05(m*, 4H); 6.96- 6.63(m*, 3H);6.10(m*, 1H); 3.89 and 3.86(s*, 3H); 3.86 and 3.70(s*, 3H); 3.69-3.49(m*, 2H); 3.24(m*, 1H); 2.48 and 2.46(d*, 2H); 1.88(m*, 1H);1.39(d*, 3H); 0.94 and 0.92(d*, 3H). 2 Me Me

MS/ESI⁺ 446-448-450 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.42(s*, 2H); 7.26(m*, 3H); 7.17(m*, 2H); 6.89(dd*, 1H); 6.82(d*, 1H);6.79(d*, 1H); 6.14(dd*, 1H); 3.89(s*, 3H); 3.80(s*, 3H); 3.61(dd*, 1H);3.58 and 3.55(ABq, 2H); 3.29(dd*, 1H). 3 Me Me

MS/ESI⁺ 472-474-476 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.45(s*, 2H); 7.34-7.26(m*, 5H); 6.79(m*, 2H); 6.68(m*, 1H); 6.15(dd*,1H); 3.89(s*, 3H); 3.80(s*, 3H); 3.49(dd*, 1H); 3.15(dd*, 1H); 1.54(m*,1H); 1.43(m*, 1H); 1.22(m*, 1H); 1.10(m*, 1H). 4 Me Me

MS/ESI⁺ 492-494-496 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.47(s*, 1H); 7.72(dd*, 1H); 7.54(d*, 1H); 7.04(dd*, 1H); 7.01(d*, 1H);6.89(d*, 1H); 6.88(d*, 1H); 6.34(dd*, 1H); 3.95(s*, 3H); 3.93(s*, 3H);3.91(s*, 3H); 3.89(s*, 3H); 3.82(dd*, 1H); 3.41(dd*, 1H). 5 CHF₂cyclopropyl- methyl

MS/ESI⁺ 637-639-641 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm); δ:8.21(s*, 2H), 7.36-7.22(m*, 3H), 7.16(m*, 3H), 7.00(m*, 2H), 6.65(dd*,1H), 6.09(dd*, 1H), 5.31(br* s*, 2H), 3.93(d*, 2H), 3.54 (dd*, 1H),3.17(dd*, 1H), 1.40(s*, 9H), 1.30(m*, 1H); 0.68(m*, 2H), 0.42(m*, 2H). 6CHF₂ cyclopropyl- methyl

MS/ESI⁺ 637-639-641 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.21(s*, 2H), 7.36-7.22(m*, 3H), 7.16(m*, 3H), 7.00(m*, 2H), 6.65(dd*,1H), 6.09(dd*, 1H), 5.31(br* s*, 2H), 3.93(d*, 2H), 3.54 (dd*, 1H),3.17(dd*, 1H), 1.40(s*, 9H), 1.30(m*, 1H); 0.68(m*, 2H), 0.42(m*, 2H). 7CHF₂ cyclopropyl- methyl

MS/ESI⁺ 537-539-541 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm, mix ofdiast.) δ: 8.49 and 8.19(s* 2H); 7.40-7.22(m*, 3H); 7.17(m*, 2H);6.97(m*, 2H); 6.63 and 6.57(dd*, 1H); 6.53(m*, 1H); 6.08 and 6.04(dd*,1H); 3.90(d*, 2H); 3.64-3.44(m*, 2H); 3.24 and 3.13(dd*, 1H); 1.22(m*,1H); 0.66(m*, 2H); 0.36(m*, 2H). 8 CHF₂ cyclopropyl- methyl

MS/ESI⁺ 537-539-541 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.25(s*, 2 H), 7.35-7.22(m*, 3 H), 7.18(m*, 3 H), 6.99(dd*, 1 H),6.94(d*, 1 H), 6.64 (dd*, 1 H), 6.10(dd*, 1 H), 4.52(s*, 1 H), 3.87(m*,2 H), 3.55(dd*, 1 H), 3.13 (dd*, 1 H), 1.74(br* s*, 2 H), 1.30(m*, 1 H),0.69 (m*, 2 H), 0.40(m*, 2 H) 9 Me cyclopentyl

MS/ESI⁺ 570-572-574 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm) δ:8.46(s*, 2H), 7.04(m*, 4H), 6.72(d*, 1H), 6.71(d*, 1H), 6.67(dd*, 1H),6.06(dd*, 1H), 4.60(m*, 1H), 3.82(s*, 3H), 3.65(q*, 1H), 3.56(dd*, 1H),3.26(dd*, 1H), 2.45(d*, 2H), 1.95- 1.75(m*, 7H), 1.70- 1.54(m*, 2H),1.39(d*, 3H), 0.91(d*, 6H) and 8.30(s*, 2H), 7.04(m*, 4H), 6.89(dd*,1H), 6.88(d*, 1H), 6.82(d*, 1H), 6.10(dd*, 1H), 4.75(m*, 1H), 3.85(s*,3H), 3.63(q*, 1H), 3.56(dd*, 1H), 3.19(dd*, 1H), 2.47(d*, 2H),1.95-1.75(m*, 7H), 1.70-1.54(m*, 2H), 1.38(d*, 3H), 0.93(d*, 6H). 10 MeMe

MS/ESI⁺ 505-507-509 [MH]⁺ 11 CHF₂ cyclopropyl- methyl

MS/ESI⁺ 644-646-648 [MH]⁺; 1H NMR (CDCl3 calibrated at 7.26 ppm):8.48(s*, 2H); 7.66(dd*, 1H), 7.58(d*, 1H); 7.21(d*, 1H); 7.19(d*, 1H);7.08(dd*, 1H); 7.04(dd*, 1H); 6.72(dd*, 1H); 6.63(dd*, 1H); 6.30(dd*,1H); 3.92(d*, 2H); 3.90(d*, 2H); 3.73(dd*, 1H); 3.39(dd*, 1H); 1.29(m*,2H); 0.68(m*, 4H); 0.38(m*, 4H). 12 CHF₂ cyclopropyl- methyl

MS/ESI⁺ 593-595-597 [MH]⁺

Example 6 Preparation of (S)-2-(4-isobutyl-phenyl)-propionic acid2-(3,5-dichloro-1-oxy-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester(Compound 13)

Compound 1 (51.5 mg, 0.1 mmoles) is dissolved in CH₂CL₂ (1 mL). m-Chloroperbenzoic acid (mCPBA, 15 mg, 0.12 mmoles) is added and the resultingsolution is stirred at room temperature for 2 hours. The mixture is thendiluted with CH₂Cl₂ (5 mL) and extracted with 1N NaOH (5 ml). Theorganic phase is dried over Na₂SO₄ and the solvent is evaporated. Thecrude is purified by preparative HPLC to yield 37 mg of the titlecompound.

The following compounds were prepared following the same route usingsuitable reagents:

TABLE 4

Compound R₁ R₂ Z—A Analytical 13 Me Me

MS/ESI⁺ 532-534-536 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm, mix ofdiast), δ: 8.11 and 7.89(s*, 2 H), 6.97- 7.10(m*, 4 H), 6.79-6.94 and6.53-6.76(m*, 3 H), 5.96 and 6.05(dd*, 1 H), 3.82 and 3.82(s*, 3 H),3.67 and 3.82(s*, 3 H), 3.60(m*, 1 H), 3.41 and 3.46(dd*, 1 H), 3.08 and3.17(dd*, 1 H), 2.43 and 2.49(d*, 2 H), 1.74- 1.93(m*, 1 H), 1.36 and1.39(d*, 3 H), 0.88 and 0.90 (d*, 6 H) 14 CHF₂ cyclopropyl- methyl

MS/ESI+ 660-662-664 [MH]⁺; 1H NMR (CDCl3 calibrated at 7.26 ppm):8.25(s*, 2 H), 7.65(dd*, 1 H), 7.57(d*, 1 H), 7.22(d*, 1 H), 7.21(d*, 1H), 7.01-7.10(m*, 2 H), 6.73(t*, 1 H), 6.63(t*, 1 H), 6.29(dd*, 1 H),3.92(d*, 2 H), 3.91(d*, 2 H), 3.73(dd*, 1 H), 3.36(dd*, 1 H), 1.18-1.43(m*, 2 H), 0.56-0.77 (m*, 4 H), 0.23-0.50(m*, 4 H) 15 CHF₂cyclopropyl- methyl

MS/ESI⁺ 609-611-613 [MH]⁺The following compounds were prepared in an analogous manner to themethods already described in earlier Examples, with appropriateselection of reagents and according to the general synthesis earlierdescribed:

Compound Chemical name 26 3-cyclopropylmethoxy-4-difluoromethoxy-benzoicacid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 27 4-(2-piperidin-1-yl-ethoxy)-benzoicacid2-(3,5-dichloro-1-oxy-pyridin-4- yl)-1-(3,4-dimethoxy-phenyl)-ethylester 28 isonicotinic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 29 nicotinic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 304-(2-imidazol-1-yl-ethoxy)-benzoic acid 1-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester31 1-(2-{4-[1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethoxycarbonyl]-phenoxy}-ethyl)-1-methyl-piperidinium 32 4-(2-morpholin-4-yl-ethoxy)-benzoicacidcyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester33 4-difluoromethoxy-3-(2-piperidin-1-yl-ethoxy)-benzoic acid 2-(3,5-dichloro-1-oxy-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester 342-(6-methoxy-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester35 4-(3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yloxy)-benzoicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 363-cyclopropylmethoxy-4-(2-piperidin-1-yl-ethoxy)-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 37 2-(6-methoxy-naphthalen-2-yl)-propionicacid 2-(3,5-dichloro-1-oxy- pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethylester 38 2-(6-methoxy-naphthalen-2-yl)-propionic acid2-(3,5-dichloro-pyridin-4- yl)-1-(3,4-dimethoxy-phenyl)-ethylester 392-(6-methoxy-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 404-amino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 412-(4-amino-phenyl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester42 4-amino-benzoic acid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 43 4-dimethylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester44 terephthalic acid mono-[1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl] ester 453-dimethylamino-4-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester46 4-imidazol-1-yl-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 474-dimethylaminomethyl-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester48 1-methyl-1H-imidazole-4-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester49 4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester50 3-(cyclopropylmethyl-methyl-amino)-4-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 514-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 52 1,2-dimethyl-1H-benzoimidazole-5-carboxylicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 53 quinoline-3-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 54(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 55 hexadecanoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 56 pentanoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 583-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 59 4-(3-cyclopropylmethyl-ureido)-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester60 quinoline-8-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 613-cyclopropylmethoxy-4-dimethylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 62 4-[3-(2-methoxy-ethyl)-ureido]-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester63 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 64 2-(2-fluoro-biphenyl-4-yl)-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester65 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester 66 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 67 2-(6-dimethylamino-naphthalen-2-yl)-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 682-(6-dimethylamino-naphthalen-2-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 693-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 704-(3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester 71 4-(3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 72 acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 73 phenyl-acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 74 butyric acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 75 4-phenyl-butyric acid1-(3-cyclopropylmethoxydifluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 764-[3-(2-dimethylamino-ethyl)-ureido]-benzoic acid 1-(3-cyclopropyl-methoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 77 6-dimethylamino-naphthalene-2-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 78 acetoxy-phenyl-acetic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 791-(3-Methanesulfonylamino-4-methoxy-phenyl)-cyclopropanecarboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 801-[3-(Cyclopropylmethyl-methyl-amino)-4-methoxy-phenyl]-cyclopropanecarboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 81 oxy-benzoicacid 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 82 2,3-dihydro-benzo[1,4]dioxine-6-carboxylicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 833-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethyl ester 843-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl ester 853,4,5-triethoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 864-fluoro-3-methoxy-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 871-methoxy-naphthalene-2-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 883,4,5-trifluoro-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 892-(2-fluoro-biphenyl-4-yl)-propionic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester90 2-oxo-thiazolidine-4-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester91 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 921-cyclopropylmethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-pheny])-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethyl ester 931-(3′,4′-dichloro-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 94 2,3-dihydro-benzo[1,4]dioxine-6-carboxylicacid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester 95 6-dimethylamino-naphthalene-2-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 961-cyclopropylmethyl-1H-indole-5-carboxylic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 974,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-l-carboxylic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 98 2-benzyloxy-propionic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester 99(3,4-dimethoxy-phenylsulfanyl)-acetic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester100 4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester 1014-[9-(4-ethyl-phenoxy)-nonyloxy]-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester

Example 7 Preparation of 2-(4-amino-phenyl)-propionic acid2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester(Compound 16)

Compound 10 (50 mg, 0.1 mmoles) is dissolved in dimethylformamide (DMF)(3 mL). Tin chloride (SnCl₂×2H₂O, 113 mg, 0.5 mmoles) is added and theresulting mixture is stirred at room temperature for 17 hours. Themixture is then diluted with water (15 mL) and extracted with Et₂O (2×30mL). The organic phase is dried over Na₂SO₄ and the solvent isevaporated. The crude is purified by preparative HPLC to yield 10 mg ofthe title compound.

TABLE 5 Compound Structure Analytical 16

MS/ESI⁺ 475-477-479 [MH]⁺; ¹H NMR (CDCl₃ calibrated at 7.26 ppm, mix ofdiast), δ: 8.31 and 8.47(s*, 2H); 6.58 and 6.90(m*, 6H): 6.76(m*, 1H);6.05 and 6.11(dd*, 1H); 3.87 and 3.89(s*, 3H); 3.72 and 3.87(s*, 3H);3.58(m*, 2H); 3.18 and 3.26(dd*, 1H); 1.33 and 1.34(d*, 3H).

Example 8 Preparation of 2-(4-methanesulphonylamino-phenyl)-propionicacid 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethyl ester(Compound 17)

Compound 16 (26 mg, 0.05 mmoles) is dissolved in dry CH₂Cl₂ (10 mL)under nitrogen atmosphere. The solution is cooled to 0° C. andtriethylamine (0.009 mL, 0.066 mmoles) and methanesulphonyl chloride(0.0052 mL, 0.06 mmoles) are added. The mixture is then allowed to reactat room temperature for 17 hours. The reaction mixture is then dilutedwith water (15 mL) and extracted with AcOEt (2×30 mL). The organic phaseis dried over Na₂SO₄ and the solvent is evaporated. The crude ispurified by preparative HPLC to yield 10 mg of the title compound as amixture of diastereoisomers.

TABLE 6 Compound Structure Analytical 17

MS/ESI⁺ 553-555-557 [MH]⁺; 1H NMR (CDCl₃ calibrated at 7.26 ppm, mix ofdiast) ppm 8.28(s*, 2 H) 7.06- 7.12(m*, 4 H) 6.97(dd*, 1 H) 6.89(d*, 1H) 6.87(d*, 1 H) 6.43(br. s., 1 H) 6.12 (dd*, 1 H) 3.90(s*, 6 H)3.59-3.70(m*, 2 H) 3.19(dd*, 1 H) 3.08(s*, 3 H) 1.36(d*, 3 H) and 1H NMR(300 MHz, CHLOROFORM-d) ppm 8.47(s*, 2 H), 7.05-7.21(m*, 4 H),6.74-6.79(m*, 2 H), 6.64-6.70(m*, 1 H), 6.30-6.38(m*, 1 H),6.03-6.18(m*, 1 H), 3.87(s*, 3 H), 3.77(s*, 3 H), 3.51-3.64 (m*, 2 H),3.27(dd*, 1 H), 3.02(s*, 3 H), 1.34-1.41(d*, 3 H)

Example 9 Preparation of1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethanol(Compound 18)

Intermediate 2b (100 mg, 0.25 mmoles) is dissolved in CHCL₃ (3 mL).m-Chloro perbenzoic acid (mCPBA, 80 mg, 0.46 mmoles) is added and theresulting solution is kept at 0° C. overnight. The mixture is thendiluted with CHCl₃ (5 mL) and washed with 1N NaOH (5 ml). The organicphase is dried over Na₂SO₄ and the solvent is evaporated. The crudeproduct is purified by crystallization with ethanol. The white solid isfiltered and washed with petroleum ether to yield 70 mg of the titlecompound.

The following compounds were prepared following the same route usingsuitable reagents:

TABLE 7

Compound R₁ R₂ Analytical 18 difluoromethyl cyclopropylmethyl MS/ESI⁺420-422-424 [MH]⁺ 19 Me cyclopropylmethyl MS/ESI⁺ 384-386-388 [MH]⁺ 20Me cyclopentyl MS/ESI⁺ 398-400-402 [MH]⁺ 21 difluoromethyldifluoromethyl MS/ESI⁺ 416-418-420 [MH]⁺ 22 difluoromethyl Me MS/ESI⁺380-382-384 [MH]⁺ 23 difluoromethyl cyclopentyl MS/ESI⁺ 434-436-438[MH]⁺ 24 Me Me MS/ESI⁺ 344-346-348 [MH]⁺

Example 10 Preparation of 4-(2-piperidin-1-yl-ethoxy)-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester hydrochloride (Compound 25)

(1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) (EDC.HCl)(55 mg, eq.) is added to a solution of compound 18 (60 mg, 0.14 mmol),4-(2-piperidin-1-yl-ethoxy)-benzoic acid (81 mg, 0.28 eq.) and4-dimethylaminopyridine (DMAP) (37 mg, 0.5 eq.) in dry DMF (4 mL) atroom temperature under nitrogen atmosphere. The mixture is stirred atroom temperature overnight, then it is treated with a saturated solutionof NH₄Cl (20 ml) and extracted with EtOAc (2×20 ml). The combinedorganic layers are dried over Na₂SO₄ and the solvent is evaporated. Thecrude is purified by preparative HPLC. The oily residue is dissolved inethyl acetate (2 ml) and added with a slight excess of a 1 M solution ofdry HCl in ethyl acetate. After evaporation of the solvent the residueis crystallized from methanol/diethyl ether to give 14 mg of thehydrochloride salt.

TABLE 8

Compound R₁ R₂ Z—A Analytical 25 CHF₂ cyclopropyl- methyl

MS/ESI⁺ 651-653-655 [MH]⁺ 1H NMR (CD₃OD calibrated at 3.31 ppm) ppm0.33-0.40(m, 2H), 0.57-0.64(m, 2H), 1.17- 1.28(m, 1H), 1.80-2.01 (m,6H), 3.03-3.14(m, 2H), 3.42-3.82(m, 6H), 3.91-3.94(d, 2H), 4.44- 4.49(t,2H), 6.31-6.37(m, 1H), 6.37-7.13(t, 1H, CHF2), 7.08-7.17(m, 5H),7.99-8.05(m, 2H), 8.42(s, 2H). Legend *NMR s = singlet d = doublet t =triplet q = quartet dd = doublet of doublets m = multiplet br = broadESI = electrospray

Pharmacological Activity Example 11 In Vitro Determination of PDE4Inhibitory Activity in the Cell Free Assay

The U937 human monocytic cell line was used as source of PDE4 enzyme.Cells were cultured, harvested and supernatant fraction preparedessentially as described in Torphy, T. J. et al., J. Pharmacol. Exp.Ther., 1992; 263:1195-1205. PDE4 activity was determined in cellssupernatants by assaying cAMP disappearance from the incubationmixtures. 50 μl of cell supernatant were incubated at 30° C. for 30minutes in a final volume of 200 μl in the presence of 1.6 μM cAMP withor without the test compound (50 μl).

The concentration of the test compounds ranged between 10⁻¹² M and 10⁻⁶M. Reactions were stopped by heat inactivation (2.5 minutes at 100° C.)and residual cAMP was measured using an electrochemiluminescence(ECL)-based immunoassay.

The results, expressed as mean±95% confidence limits of the molarconcentration of the test compound producing 50% inhibition of cAMPdisappearance (IC₅₀) are reported in Table 9 of Example 12. Percentageof inhibition of PDE4 activity was calculated, assuming cAMPdisappearance in the absence of inhibitors as 100% and cAMPdisappearance in heat inactivated samples as 0%. All the IC₅₀ values ofthe tested compounds, representative of the invention, were less than0.2 microM.

Example 12 In vitro determination of PDE4 inhibitory activity in theperipheral blood mononuclear cells (PBMCs) assay

The assay, which is based on the known inhibitory activity exerted byPDE4 inhibitors on the lipopolyshaccarides (LPS)-induced tumour necrosisfactor-alpha (TNF-α release in peripheral blood mononuclear cells(PBMCs), was performed according to a method previously described(Hatzelmann A. et al., J. Pharmacol. Exp. Ther., 2001; 297:267-279;Draheim R. et al., J. Pharmacol. Exp. Ther., 2004; 308:555-563.Cryopreserved human PBMCs, (100 μl/well) were incubated in 96-wellplates (10⁵ cells/well), for 30 min, in the presence or absence (50microl) of the test compounds whose concentrations ranged from 10⁻¹² Mto 10⁻⁶ M. Subsequently, LPS (3 ng/ml) was added. After 18 hours ofincubation at 37° C. in a humidified incubator under an atmosphere of95% air and 5% CO₂, culture medium was collected and TNF-αc measured byELISA. The results, expressed as mean±95% confidence limits of the molarconcentration of the test compound producing 50% inhibition ofLPS-induced TNF-a release (IC₅₀) are reported in Table 9.

The effects of the tested compounds were calculated as percentage ofinhibition of TNF-αrelease, assuming LPS-induced TNF-α production in theabsence of inhibitor compound as 100% and basal TNF-α production ofPBMCs in the absence of LPS as 0%.

TABLE 9 In vitro PDE4 inhibition activity of representative compounds ofthe invention. IC50 cell free IC50 PBMCS Compound (nM) (nM) 1 118 69 2 —89 3 118 52 4 3.4 34.2 6 9 95 7 7 99 8 22 — 9 22 85 11 12 51 12 12 45613 1.5 13 14 0.2 2 15 8.6 15 16 6.3 36

Example 13 Evaluation of the Ability to Inhibit the Low Affinity LPDE4Versus the Ability to Compete for the High Affinity HPDE4

The affinity toward LPDE4 and HPDE4 was assessed as previously describedrespectively in Cortijo J. et al., Br. J. Pharmacol., 1993, 108: 562-568and Duplantier A. J. et al., J. Med. Chem., 1996; 39: 120-125. Theconcentration of the test compound ranged between 10⁻¹² M and 10⁻⁵ M.The results in terms of IC₅₀ are reported in Table 10. In the case ofLPDE4, the IC₅₀ is the molar concentration of the test compoundproducing 50% inhibition of cAMP disappearance, while in the case ofHPDE4, the IC₅₀ is the molar concentration of the test compoundproducing 50% inhibition of the binding of [H³] rolipram. The resultsindicate that the compounds of the invention inhibited LPDE4 withsubnanomolar affinity and are considerably more selective toward LPDE4versus HPDE4.

TABLE 10 Activity profile of representative compounds of the inventionHPDE4 LPDE4 Compound IC₅₀ (nM) IC₅₀ (nM) HPDE4/LPDE4 14 13.9 0.0881 15815 2.17 0.169 273 20 299 0.759 394 9 399 0.738 541 11 153 0.116 1319

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1: A method of treating a disease of the respiratory tract characterizedby airway obstruction, said method comprising administering to a subjectin need thereof an effective amount of a compound of formula (I):

wherein: Z is selected from the group consisting of (CH₂)_(m);(CH₂)_(n)O; O(CH₂)_(p); CH₂SO₂; CHNR₆; CH₂NR₆; NR₆; OCOR₄R₅; and CR₄R₅,wherein m=0, 1, or 2; n=1, 2, or 3; p=0, 1, 2 or 3; R₄ is independentlyselected from H or a linear or branched (C₁-C₄) alkyl, optionallysubstituted by one or more halogen atoms or a (C₁-C₄) cycloalkyl; R₅ isindependently selected from the group consisting of linear or branched(C₁-C₄) alkyl optionally substituted by one or more halogen atoms;phenyl; benzyl; NH₂; and HNCOOR′, wherein R′ is linear or branched(C₁-C₄) alkyl optionally substituted by one or more halogen atoms; R₆ isH or a linear or branched (C₁-C₄) alkyl optionally substituted by one ormore halogen atoms; R₁ and R₂ are the same or different and are eachindependently selected from the group consisting of H; linear orbranched (C₁-C₆) alkyl, optionally substituted by one or moresubstituents selected from the group consisting of a halogen atom,(C₃-C₇) cycloalkyl and (C₅-C₇) cycloalkenyl; (C₃-C₇) cycloalkyl; (C₅-C₇)cycloalkenyl; linear or branched (C₂-C₆) alkenyl; and linear or branched(C₂-C₆) alkynyl; R₃ is one or more substituents independently selectedfrom the group consisting of H, CN, NO₂, CF₃ and a halogen atom; A is amono- or bicyclic, saturated, partially unsaturated, or unsaturated ringsystem, having 5 to 10 ring atoms, which may be optionally substitutedwith one or more R_(x) groups, wherein each R_(x) may be the same ordifferent and each R_(x) is independently selected from the groupconsisting of: linear or branched (C₁-C₆) alkyl optionally substitutedby one or more halogen atoms or (C₃-C₇) cycloalkyl; linear or branched(C₂-C₆) alkenyl optionally substituted by one or more (C₃-C₇)cycloalkyl; linear or branched (C₂-C₆) alkynyl optionally substituted byone or more (C₃-C₇) cycloalkyl; (C₅-C₇) cycloalkenyl; phenyl; (C₃-C₇)heterocycloalkyl; OR₇, wherein R₇ is selected from the group consistingof: H; (C₁-C₁₀) alkyl optionally substituted by one or more halogenatoms or (C₃-C₇) cycloalkyl; (C₃-C₇) cycloalkyl; (C₁-C₄)alkylene-(C₃-C₇) heterocycloalkyl; CO(C₁-C₆) alkyl optionallysubstituted by one or more halogen atoms; COO(C₁-C₆) alkyl optionallysubstituted by one or more halogen atoms; phenyl; benzyl; (C₁-C₁₀)alkylene-NR₈R₉, wherein R₈ and R₉ are each independently selected fromthe group consisting of H, linear or branched (C₁-C₆) alkyl optionallysubstituted by one or more halogen atoms, or R₈ and R₉ together with thenitrogen atom to which they are linked form a saturated, partiallysaturated, or unsaturated ring, optionally substituted by (C₁-C₄) alkyloptionally substituted by one or more halogen atoms; a halogen atom; CN;NO₂; NR₁₀R₁₁, wherein R₁₀ and R₁₁ may be the same or different and areeach independently selected from the group consisting of: H; linear orbranched (C₁-C₆) alkyl, optionally substituted with one or more halogenatoms, phenyl or (C₃-C₇) cycloalkyl; COC₆H₅; CO—(C₁-C₄) alkyl optionallysubstituted by one or more halogen atoms; COO—(C₁-C₄) alkyl optionallysubstituted by one or more halogen atoms; CONH—(C₁-C₆) alkylene-R₁₂,wherein R₁₂ is selected from the group consisting of H; (C₁-C₄) alkyloptionally substituted by one or more halogen atoms; and OR₄R₅; andCONH(C₁-C₄) alkylene-N(C₁-C₄) alkyl optionally substituted by one ormore halogen atoms; or R₁₀ and R₁₁ together with the nitrogen atom towhich they are linked form a saturated or partially saturated ring;(C₁-C₄) alkylene-NR₁₀R₁₁; COR₁₂, wherein R₁₂ is phenyl or linear orbranched (C₁-C₆) alkyl optionally substituted by one or more halogenatoms; oxo; HNSO₂R₁₃, wherein R₁₃ is (C₁-C₄) alkyl optionallysubstituted by one or more halogen atoms or a phenyl optionallysubstituted with one or more halogen atoms or with a (C₁-C₄) alkyl groupoptionally substituted by one or more halogen atoms; SO₂R₁₄, wherein R₁₄is (C₁-C₄) alkyl, OH, or NR₁₀R₁₁ wherein R₁₀ and R₁₁ are as definedabove; SOR₁₅, wherein R₁₅ is phenyl or (C₁-C₄) alkyl optionallysubstituted by one or more halogen atoms; SR₁₆, wherein R₁₆ is H,phenyl, or (C₁-C₄) alkyl optionally substituted by one or more halogenatoms; COOR₁₇, wherein R₁₇ is H, (C₁-C₄) alkyl optionally substituted byone or more halogen atoms, phenyl, or benzyl; and (CH₂)_(q)OR₁₈, whereinq=1, 2, 3, or 4 and R₁₈ is H or (C₁-C₄) cycloalkyl, or apharmaceutically acceptable salt thereof or a N-oxide of the pyridinering thereof. 2: A method according to claim 1, wherein R₄ is methyl. 3:A method according to claim 1, wherein R₅ is methyl. 4: A methodaccording to claim 1, wherein R′ is t-butyl. 5: A method according toclaim 1, wherein A is an aryl group, a (C₃-C₈) cycloalkyl group, or aheteroaryl group. 6: A method according to claim 1, wherein in A atleast one ring atom is a heteroatom. 7: A method according to claim 1,wherein in A at least one ring atom is a heteroatom selected from N, S,and O. 8: A method according to claim 1, wherein R₈ and R₉ together withthe nitrogen atom to which they are linked form a piperidine ringoptionally substituted by (C₁-C₄) alkyl optionally substituted by one ormore halogen atoms, an oxazine ring optionally substituted by (C₁-C₄)alkyl optionally substituted by one or more halogen atoms, or animidazole ring optionally substituted by (C₁-C₄) alkyl optionallysubstituted by one or more halogen atoms. 9: A method according to claim1, wherein R₁₀ and R₁₁ together with the nitrogen atom to which they arelinked form a piperidyl ring. 10: A method according to claim 1, whereinA is a phenyl optionally substituted with one or more R_(x) groups. 11:A method according to claim 1, wherein A is a heteroaryl ring optionallysubstituted with one or more R_(x) groups. 12: A method according toclaim 11, wherein A is a heteroaryl ring selected from the groupconsisting of pyrrole, pyrazole, furan, thiophene, imidazole, oxazole,isoxazole, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, andpyran. 13: A method according to claim 1, wherein R₃ is a halogen atom.14: A method according to claim 13, wherein R₃ is chlorine. 15: A methodaccording to claim 14, which comprises administering an effective amountof a compound of formula (II):

or a pharmaceutically acceptable salt thereof or a N-oxide of thepyridine ring thereof. 16: A method according to claim 15, wherein Z is(CH₂)_(m) with m equal to
 0. 17-18. (canceled) 19: A method according toclaim 15, wherein Z is CHR₅ where R₅ is a linear or branched C₁-C₄ alkyloptionally substituted by one or more halogen atoms. 20: A methodaccording to claim 15, wherein Z is CR₄R₅ where R₄ and R₅ are the sameor different and are each independently linear or branched C₁-C₄ alkyloptionally substituted by one or more halogen atoms or they form a ringwith the carbon atom to which they are linked having 3, 4, 5 or 6 carbonatoms. 21: A method according to claim 15, wherein Z is CR₄R₅ where R₄and R₅ together with the carbon atom to which they are linked form aring having 3 carbon atoms.
 22. (canceled) 23: A method of treating adisease of the respiratory tract characterized by airway obstruction,said method comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition, comprising at leastone compound, salt, or N-oxide of claim 1 and one or morepharmaceutically acceptable carriers and/or excipients. 24: A methodaccording to claim 23, wherein said pharmaceutical composition isadministered by inhalation. 25: A method according to claim 23, whereinsaid pharmaceutical composition further comprises an additional activeingredient selected from the group consisting of a beta₂-agonist, acorticosteroid, an anticholinergic agent, and an antimuscarinic agent.26-27. (canceled) 28: A method according to claim 1, wherein saiddisease is selected from the group consisting of asthma, chronicbronchitis, and chronic obstructive pulmonary disease.
 29. (canceled)30: A method according to claim 1, wherein said administering is byinhalation. 31: A method according to claim 28, wherein saidadministering is by inhalation. 32: A compound of formula (2):

wherein: R₁ is: H; linear or branched (C₁-C₆)alkyl, optionallysubstituted by one or more substituents selected from the groupconsisting of a halogen atom, (C₃-C₇)cycloalkyl, and(C₅-C₇)cycloalkenyl; (C₃-C₇)cycloalkyl; (C₅-C₇)cycloalkenyl; linear orbranched (C₂-C₆)alkenyl; or linear or branched (C₂-C₆)alkynyl; R₂ iscyclopropylmethyl; and R₃ is one or more substituents independentlyselected from the group consisting of H, CN, NO₂, CF₃ and a halogenatom, or an N-oxide on the pyridine ring thereof. 33: A compound orN-oxide according to claim 32, wherein R₁ is selected from the groupconsisting of methyl and difluoromethyl; and R₃ is two chlorine atoms onthe 3- and 5-positions of the pyridine ring to which they are bonded.34: A compound or N-oxide according to claim 32, which is an N-oxide onthe pyridine ring. 35: A compound or N-oxide according to claim 32,which is not an N-oxide on the pyridine ring. 36: A compound or N-oxideaccording to claim 33, which is an N-oxide on the pyridine ring. 37: Acompound or N-oxide according to claim 33, which is not an N-oxide onthe pyridine ring.